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1. Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates

Author

Frank Herrmann, Manuela Hessmann, Sabine Schaertl, Karola Berg-Rosseburg, Christopher J Brown, Galina Bursow, Anass Chiki, Andreas Ebneth, Miriam Gehrmann, Nicole Hoeschen, Madlen Hotze, Stefanie Jahn, Peter D Johnson, Vinod Khetarpal, Alex Kiselyov, Karsten Kottig, Stefanie Ladewig, Hilal Lashuel, Sven Letschert, Matthew R Mills, Kathrin Petersen, Michael E Prime, Christoph Scheich, Gerhard Schmiedel, John Wityak, Longbin Liu, Celia Dominguez, Ignacio Muñoz-Sanjuán, and Jonathan A Bard

Subjects
Medicine, Science
Abstract

Abstract Huntington’s disease (HD) is caused by a CAG trinucleotide repeat expansion in the first exon of the huntingtin (HTT) gene coding for the huntingtin (HTT) protein. The misfolding and consequential aggregation of CAG-expanded mutant HTT (mHTT) underpin HD pathology. Our interest in the life cycle of HTT led us to consider the development of high-affinity small-molecule binders of HTT oligomerized/amyloid-containing species that could serve as either cellular and in vivo imaging tools or potential therapeutic agents. We recently reported the development of PET tracers CHDI-180 and CHDI-626 as suitable for imaging mHTT aggregates, and here we present an in-depth pharmacological investigation of their binding characteristics. We have implemented an array of in vitro and ex vivo radiometric binding assays using recombinant HTT, brain homogenate-derived HTT aggregates, and brain sections from mouse HD models and humans post-mortem to investigate binding affinities and selectivity against other pathological proteins from indications such as Alzheimer’s disease and spinocerebellar ataxia 1. Radioligand binding assays and autoradiography studies using brain homogenates and tissue sections from HD mouse models showed that CHDI-180 and CHDI-626 specifically bind mHTT aggregates that accumulate with age and disease progression. Finally, we characterized CHDI-180 and CHDI-626 regarding their off-target selectivity and binding affinity to beta amyloid plaques in brain sections and homogenates from Alzheimer’s disease patients.

Published
2021
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2. Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates

Author

Madlen Hotze, Miriam Gehrmann, Manuela Hessmann, Longbin Liu, Christoph Scheich, Kathrin Petersen, Nicole Hoeschen, Peter Johnson, Sabine Schaertl, Stefanie Jahn, Matthew R. Mills, Ignacio Munoz-Sanjuan, Alex S. Kiselyov, John Wityak, Anass Chiki, Vinod Khetarpal, Karsten Kottig, Gerhard Schmiedel, Galina Bursow, Stefanie Ladewig, Christopher J. Brown, Karola Berg-Rosseburg, Michael Prime, Sven Letschert, Andreas Ebneth, Jonathan Bard, Celia Dominguez, Frank Herrmann, and Hilal A. Lashuel

Subjects
exon-1, Huntingtin, Mutant, law.invention, Mice, Radioligand Assay, amyloid fibrils, Exon, law, alzheimers-disease, Huntingtin Protein, dysfunction, Multidisciplinary, Chemistry, Immunohistochemistry, Recombinant Proteins, Cell biology, small molecules, Huntington Disease, Recombinant DNA, Medicine, Preclinical imaging, congenital, hereditary, and neonatal diseases and abnormalities, brain, Science, Mice, Transgenic, Protein Aggregation, Pathological, Article, Protein Aggregates, Alzheimer Disease, mental disorders, Animals, Humans, Radioactive Tracers, beta-sheet structure, Pharmacology, Nitrogen Radioisotopes, toxicity, In vitro, nervous system diseases, Disease Models, Animal, polyglutamine aggregation, Positron-Emission Tomography, Diseases of the nervous system, Autoradiography, identification, Radiopharmaceuticals, Trinucleotide repeat expansion, Biomarkers, Ex vivo
Abstract

Huntington’s disease (HD) is caused by a CAG trinucleotide repeat expansion in the first exon of the huntingtin (HTT) gene coding for the huntingtin (HTT) protein. The misfolding and consequential aggregation of CAG-expanded mutant HTT (mHTT) underpin HD pathology. Our interest in the life cycle of HTT led us to consider the development of high-affinity small-molecule binders of HTT oligomerized/amyloid-containing species that could serve as either cellular and in vivo imaging tools or potential therapeutic agents. We recently reported the development of PET tracers CHDI-180 and CHDI-626 as suitable for imaging mHTT aggregates, and here we present an in-depth pharmacological investigation of their binding characteristics. We have implemented an array of in vitro and ex vivo radiometric binding assays using recombinant HTT, brain homogenate-derived HTT aggregates, and brain sections from mouse HD models and humans post-mortem to investigate binding affinities and selectivity against other pathological proteins from indications such as Alzheimer’s disease and spinocerebellar ataxia 1. Radioligand binding assays and autoradiography studies using brain homogenates and tissue sections from HD mouse models showed that CHDI-180 and CHDI-626 specifically bind mHTT aggregates that accumulate with age and disease progression. Finally, we characterized CHDI-180 and CHDI-626 regarding their off-target selectivity and binding affinity to beta amyloid plaques in brain sections and homogenates from Alzheimer’s disease patients.

Published
2021

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